Antioxidant-inspired drug discovery: antitumor metabolite is formed in situ from a hydroxycinnamic acid derivative upon free radical scavenging.
2019
Аутори:
Fási, LauraDi Meo, Florent
Kuo, Ching-Ying
Stojković Burić, Sonja
Martins, Ana
Kúsz, Norbert
Béni, Zoltán
Dékány, Miklós
Balogh, György Tibor
Pešić, Milica
Wang, Hui-Chun
Trouillas, Patrick
Hunyadi, Attila
Тип документа:
Чланак у часопису (Објављена верзија)
,
© 2019 American Chemical Society.
Метаподаци
Приказ свих података о документуАпстракт:
Cancer cells generally possess higher levels of reactive oxygen species than normal cells, and this can serve as a possible therapeutic target. In this proof-of-concept study, an antioxidant-inspired drug discovery strategy was evaluated using a hydroxycinnamic acid derivative. The processing of oxidized mixtures of p-coumaric acid methyl ester (pcm) revealed a new antitumor lead, graviquinone. Graviquinone bypassed ABCB1-mediated resistance, induced DNA damage in lung carcinoma cells but exerted DNA protective activity in normal keratinocytes, and modulated DNA damage response in MCF-7 cells. The cytotoxic effect of pcm in MCF-7 cells was potentiated under H2O2-induced oxidative stress, and the formation of graviquinone was confirmed by Fenton's reaction on pcm. In silico DFT calculations suggested graviquinone as a kinetic product of pcm scavenging •OH radicals. Our results demonstrate the pharmacological value of an in situ-formed, oxidative stress-related metabolite of an antioxidant. This might be of particular importance for designing new strategies for antioxidant-based drug discovery.
Извор:
Journal of Medicinal Chemistry, 2019, 62, 3, 1657-1668Финансирање / пројекти:
- COST Action CM1407
- National Research, Developmentand Innovation Office, Hungary (NKFIH; K119770)
- Ministryof Human Capacities, Hungary grant 20391-3/2018/FEKUS-TRAT
- Czech ScienceFoundation (P208/12/G016
- National Program ofSustainability I from the Ministry-of-Youth, Education andSports of the Czech Republic (LO1305)
- UNKP-18-4 New National Excellence Program of theMinistry of Human Capacitie
- János Bolyaifellowship of the Hungarian Academy of Sciences
- Kálmán Szász Prize
- ungarian Academy ofSciences
- Ministry of Science and Technology, Taiwan(MOST 107-2911-I-037-502)
DOI: 10.1021/acs.jmedchem.8b01994
ISSN: 0022-2623
PubMed: 30615450
WoS: 000459223600036
Scopus: 2-s2.0-85061622730
URI
http://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01994https://radar.ibiss.bg.ac.rs/handle/123456789/3278